The purpose of this proposal is to cultivate the scientific development and advance the research skills of Dr. Anna Hemnes, so that she may become an independent investigator. Dr. Hemnes is currently developing her academic career in the Center for Lung Research at Vanderbilt University Medical Center (VUMC). VUMC provides an environment conducive to developing physician-scientists through its many laboratory resources, educational opportunities, and expert faculty. Under guidance by Dr. John Newman, Dr. Hemnes will design and perform experiments that will enhance her knowledge and research skills in the pathobiology of right ventricular response to afterload stress. Through laboratory experience and formal coursework, she will gain expertise in experimental design and execution, transgenic murine model use, cell and molecular biology techniques, statistical analysis, and data reporting. These skills will provide the foundation for Dr. Hemnes to pursue an independent academic career in right ventricular research. Right ventricular (RV) stress responses are a major determinant of survival in advanced pulmonary hypertension but little studied due to non-standard pulmonary vascular obstruction leading to right ventricular stress. We have developed a model of RV hypertrophy by banding the main pulmonary artery. In preliminary data we present evidence that RV afterload stress responses are gender dependent and that gender alters RV response to endothelin antagonism. We hypothesize that estrogen is protective in the RV responses to afterload stress and that endothelin and sex hormones interact to generate morphologic, physiologic, and biochemical RV responses to afterload stress that are different in males and females. To test this hypothesis, we have developed the following specific aims: 1) To determine the effects of sex hormones on afterload-induced RV hypertrophy and modification endothelin signaling in RV cardiomyocytes in this context; 2) To define the effects of endothelin on the afterload-stressed RV and on intracellular estrogen signaling within the cardiomyocyte. RV failure is an important consequence of many cardiopulmonary disorders and a major determinant of mortality. The gender differences in RV response to afterload stress require further exploration and explanation. The higher predisposition of human females to PAH and the use of endothelin blockade in pulmonary arterial hypertension gives this research clinical relevance and biologic importance.